Formulation for inhalation

ABSTRACT

A dry powder composition comprising budesonide and a carrier substance, both of which are in finely divided form, wherein the formulation has a poured bulk density of from 0.28 to 0.38 g/ml is useful in the treatment of respiratory disorders.

FIELD OF THE INVENTION

The present invention provides a new pharmaceutical formulation, itspreparation and its use.

BACKGROUND OF THE INVENTION

Potent drugs for administration by inhalation are generally formulatedin association with carriers such as lactose because of the problem ofpreparing accurate doses. When such drugs are diluted, variations in theweight of the formulation result in a smaller drug dosage variation ratecompared with when they are not diluted. These formulations havegenerally consisted of coarse particles of the carrier with fineparticles of the drug, which combination is generally known as anordered mixture.

The invention provides an improved formulation which, in systemsdesigned to imitate inhalation has been found to give an improveddispersion of the drug.

DESCRIPTION OF THE INVENTION

According to the invention there is provided a dry powder compositioncomprising budesonide and a carrier substance, both of which are infinely divided form, wherein the formulation has a poured bulk densityof from 0.28 to 0.38 g/ml, preferably from 0.30 to 0.36 g/ml.

The poured bulk density according to the present invention is measuredusing known techniques, for example those described in "Powder testingguide: Methods of measuring the physical properties of Bulk powders" L.Svarovsky, Elsevier Applied Science 1987, pp 84-86.

The carrier substance is preferably a mono-, di- or polysaccharide, asugar alcohol or another polyol. Suitable carriers are, for example,lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose,sucrose, mannitol; and starch. Lactose is particularly preferred,especially in the form of its monohydrate.

The ingredients of the formulation according to the invention must bothbe in a finely divided form, i.e. their mass median diameter shouldgenerally be less than 10 μm, preferably from 1 to 7 μm, as measured bya laser diffraction instrument or a coulter counter. The ingredients maybe produced in the desired particle size using methods known to those ofskill in the art, e.g. milling, micronisation or direct precipitation.

The composition according to the invention is preferably formulated tocomprise, as a daily dose, from 20 to 4300 μg of budesonide (preferablyfrom 80 to 2150 μg). More preferably the composition is formulated toprovide unit doses of 200 μg or 400 μg of budesonide. The composition ispreferably formulated to comprise in each unit dose from 50 μg to 25 mgof the carrier substance, more preferably from 50 μg to 10 mg, mostpreferably from 100 to 4000 μg.

According to the invention there is further provided a process forpreparing a composition according to the invention which comprises

(a) micronising budesonide and the carrier substance;

(b) optionally conditioning the product; and

(c) spheronizing until the desired bulk density is obtained.

The process preferably further comprises a low energy remicronisationstep after step (b).

The formulation according to the invention may be made by conventionaltechniques known per se. Such production processes generally comprisemicronising the ingredients to the required size, removing any amorphousareas on the particles obtained by, for example, the methods describedin WO 92/18110 or WO 95/05805 and then agglomerating, spheronising andsieving the powder obtained. The size of the agglomerates obtained ispreferably in the range of from 100 to 2000 μm, more preferably from 100to 800 μm. The bulk density of the formulation produced may be adjustedby varying the components and the process empirically, for example thebulk density can be increased by lengthening the time in which theparticles are tumbled in a spheronising device.

In solid-solid mixing, one of the most important features is to ensurecontent uniformity. The major problem encountered in the powder mixingof fine powders is the inability of mixers to break down powderagglomerates. It has been found that a remicronisation step after theconditioning step of the fine powder with low energy input isadvantageous. It should generally be carried out using enough energy tobreak down powder agglomerates but not with so much energy that the sizeof the particles themselves is affected. Such a step gives a compositionwherein the active substance and carrier substance are substantiallyuniformly distributed, having for example a relative standard deviationof less than 3% (preferably less than 1%) without disturbing thecrystallinity of the fine particles.

The formulation according to the invention may be administered using anyknown dry powder inhaler, for example the inhaler may be a single or amulti dose inhaler, and may be a breath actuated dry powder inhaler, forexample Turbuhaler (trade mark). The invention further provides use of acomposition according to the invention in the manufacture of amedicament for use in therapy. The composition according to theinvention is useful in the treatment of respiratory disorders,particularly asthma. The invention also provides a method of treating apatient suffering from a respiratory disorder which comprisesadministering to the patient a therapeutically effective amount of acomposition according to the invention.

The invention is illustrated, but not limited, by reference to thefollowing Example.

EXAMPLE

9 Parts of budesonide and 91 parts of lactose monohydrate weremicronised separately in a spiral jet mill at a pressure of about 6-7bars to give a particle size of less than 3 μm before being mixedthoroughly in a Turbula mixer. Before mixing, the lactose monohydratepowder was conditioned according to the method described in WO 95/05805.The mixture was remicronised in a spiral jet mill at a pressure of onlyabout 1 bar to obtain a uniform mixture. The powder was thenagglomerated by feeding the powder into a twin screw feeder (K-Tron),sieving in an oscillating sieve (0.5 mm mesh size), spheronising in arotating pan with a peripheral speed of 0.5 m/s for 4 minutes and thensieving again using the same sieve, then spheronising once more for 6minutes before final sieving (mesh size 1.0 mm) giving a powder with abulk density of 0.35 g/ml.

I claim:
 1. A dry powder pharmaceutical composition comprisingbudesonide and a carrier substance,wherein both the budesonide and thecarrier substance consist of particles having a mass median diameter ofless than 10 μm, and the composition has a poured bulk density of from0.28 to 0.38 g/ml.
 2. A composition according to claim 1 wherein thebulk density is from 0.30 to 0.36 g/ml.
 3. A composition according toclaim 1 wherein the active substance and carrier substance aresubstantially uniformly distributed.
 4. A composition according to claim1 for use in the treatment of a respiratory disorder.
 5. A process forpreparing a composition according to claim 1 which comprises(a)micronising budesonide and the carrier substance; (b) optionallyconditioning the product; and (c) spheronizing until the desired bulkdensity is obtained.
 6. A process according to claim 5 which comprises alow energy remicronisation step after step (b).
 7. A method of treatinga patient suffering from a respiratory disorder which comprisesadministering to the patient a therapeutically effective amount of acomposition according to claim
 1. 8. A composition according to claim 1wherein said carrier substance is selected from the group consisting ofmonosaccharides, disaccharides, polysaccharides and polyols.
 9. Acomposition according to claim 1 wherein the carrier substance isselected from the group consisting of lactose, glucose, raffinose,melezitose, lactitol, maltitol, trehalose, sucrose, mannitol and starch.10. A composition according to claim 9 wherein said carrier substance islactose monohydrate.
 11. A composition according to claim 1 wherein themass median diameter of the particles of budesonide and carrier is from1 to 7 μm.
 12. A process according to claim 6, wherein the mass mediandiameter lies in the range of from 1 to 7 μm.
 13. A process according toclaim 6, wherein the bulk density is from 0.30 to 0.36 g/ml.
 14. Aprocess according to claim 6, wherein the budesonide and the carriersubstance are substantially uniformly distributed.